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Mechanisms of Resistance

Genomic Analysis Reveals a Point Mutation in the Two-Component Sensor Gene graS That Leads to Intermediate Vancomycin Resistance in Clinical Staphylococcus aureus

Benjamin P. Howden, Timothy P. Stinear, David L. Allen, Paul D. R. Johnson, Peter B. Ward, John K. Davies
Benjamin P. Howden
1Australian Bacterial Pathogenesis Program, Department of Microbiology, Monash University, Wellington Rd., Clayton, Victoria, Australia
2Infectious Diseases
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  • For correspondence: Benjamin.Howden@austin.org.au
Timothy P. Stinear
1Australian Bacterial Pathogenesis Program, Department of Microbiology, Monash University, Wellington Rd., Clayton, Victoria, Australia
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David L. Allen
1Australian Bacterial Pathogenesis Program, Department of Microbiology, Monash University, Wellington Rd., Clayton, Victoria, Australia
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Paul D. R. Johnson
2Infectious Diseases
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Peter B. Ward
3Microbiology Departments, Austin Health, Heidelberg, Victoria, Australia
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John K. Davies
1Australian Bacterial Pathogenesis Program, Department of Microbiology, Monash University, Wellington Rd., Clayton, Victoria, Australia
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DOI: 10.1128/AAC.01613-07
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ABSTRACT

Methicillin-resistant Staphylococcus aureus (MRSA), once restricted to hospitals, is spreading rapidly through the wider community. Resistance to vancomycin, the principal drug used to treat MRSA infections, has only recently emerged, is mainly low level, and characteristically appears during vancomycin therapy (vancomycin-intermediate S. aureus [VISA] and hetero-resistant VISA). This phenomenon suggests the adaptation of MRSA through mutation, although defining the mutations leading to resistance in clinical isolates has been difficult. We studied a vancomycin-susceptible clinical MRSA isolate (MIC of 1 μg/ml) and compared it with an isogenic blood culture isolate from the same patient, despite 42 days of vancomycin treatment (MIC of 4 μg/ml). A whole-genome sequencing approach allowed the nearly complete assembly of the genome sequences of the two isolates and revealed only six nucleotide substitutions in the VISA strain compared with the parent strain. One mutation occurred in graS, encoding a putative two-component regulatory sensor, leading to a change from a polar to a nonpolar amino acid (T136I) in the conserved histidine region of the predicted protein. Replacing the graS allele of the vancomycin-susceptible parent strain with the graS allele from the VISA derivative resulted in increased vancomycin resistance at a level between those of the vancomycin-susceptible S. aureus and VISA clinical isolates, confirming a role for graRS in VISA. Our study suggests that MRSA is able to develop clinically significant vancomycin resistance via a single point mutation, and the two-component regulatory system graRS is a key mediator of this resistance. However, additional mutations are likely required to express the full VISA phenotype.

  • Copyright © 2008 American Society for Microbiology
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Genomic Analysis Reveals a Point Mutation in the Two-Component Sensor Gene graS That Leads to Intermediate Vancomycin Resistance in Clinical Staphylococcus aureus
Benjamin P. Howden, Timothy P. Stinear, David L. Allen, Paul D. R. Johnson, Peter B. Ward, John K. Davies
Antimicrobial Agents and Chemotherapy Sep 2008, 52 (10) 3755-3762; DOI: 10.1128/AAC.01613-07

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Genomic Analysis Reveals a Point Mutation in the Two-Component Sensor Gene graS That Leads to Intermediate Vancomycin Resistance in Clinical Staphylococcus aureus
Benjamin P. Howden, Timothy P. Stinear, David L. Allen, Paul D. R. Johnson, Peter B. Ward, John K. Davies
Antimicrobial Agents and Chemotherapy Sep 2008, 52 (10) 3755-3762; DOI: 10.1128/AAC.01613-07
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KEYWORDS

Genes, Bacterial
Point Mutation
Staphylococcus aureus
vancomycin resistance

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